Many inflammatory processes directly impact the function of the central nervous system (CNS) and give rise to human diseases. For example, acute infection of the CNS can induce a variety of disease states such as meningitis and encephalitis. One of our main interests is to mechanistically define the impact of acute infections on the CNS and establish treatments to ameliorate adverse symptoms associated with these infections. We study viral (lymphocytic choriomeningitis virus, vesicular stomatitis virus) and parasitic (plasmodium berghei) infections to identify the similarities and differences in how the immune system responds to these unique challenges. We also study sterile inflammatory responses (i.e., traumatic brain injury) to provide insights into how CNS immune cells respond to damage in the absence of an infectious agent. To advance our understanding of neural-immune interactions during CNS inflammatory diseases, we utilize a contemporary approach referred to as intravital two-photon laser scanning microscopy (TPM), which allows us to watch immune cells operate in the living brain in real-time. This is accomplished by using fluorescently tagged immune cells and pathogens. Use of fluorescent tags allows us to study the dynamics of innate (e.g. microglia, monocytes, macrophages, neutrophils, dendritic cells) and adaptive (e.g. microbe-specific CD8 T cells, CD4 T cells, B cells) immune cells as a disease develops. We can also administer therapeutic compounds into the viewing window (transcranial delivery) and watch how this locally influences the inflammatory process in real-time. This powerful approach allows us to evaluate the efficacy of potential therapeutics at the site of disease. To gain novel insights into sterile immune responses in the brain, we recently developed a focal model of mild traumatic brain injury (mTBI) referred to as meningeal compression injury. Traumatic brain injuries in humans range from mild to severe and are quite diverse in nature. Our meningeal compression model reflects one type of injury among a broad spectrum. The injury is mild, focal, and occurs beneath a closed-skull. Importantly, this injury model is advantageous because it can be closely monitored by TPM and is readily amenable to local therapeutic manipulation. Using TPM we initially set out to define the pathology and innate immune reaction to focal brain injury in real-time. Following mTBI, we observed that meningeal blood vessels and macrophages were damaged within the first 30 minutes. Some vessels were occluded while others began to leak their contents into the subarachnoid space. Importantly, the vascular pathology was comparable to what was observed in humans following mTBI. We also showed that the glial limitans becomes porous following injury due to destruction of astrocytes, resulting in leakage of cerebral spinal fluid into the brain parenchyma. Destruction of the glial limitans may help explain the kinetics of cell death, which was first observed in the meninges and later spread into the parenchyma over time. The innate immune response to mTBI within the first 12 hours was characterized by a specialized microglia reaction in the brain parenchyma and the recruitment of myelomonocytic cells (monocytes and neutrophils) into the meninges. These responses were likely partitioned to maximize efficiency of the innate immune system as it attempted to deal separately with two injured, but anatomically distinct CNS environments: meninges and parenchyma. Both immune reactions were driven by purinergic receptor signaling and appeared to be neuroprotective. When the responses were inhibited, an increase in cell death was observed. To pharmacologically manipulate the mTBI reaction locally, we developed a new approached referred to as transcranial drug delivery. We discovered that the intact skull bone allows passage of low molecular weight compounds (<40,000 MW) into the underlying meninges and brain tissue. Using this approach we set out to identify and therapeutically eliminate the primary driver of mTBI lesion pathogenesis. We observed by TPM that reactive oxygen species (ROS) were generated almost immediately after injury. As a therapy, we applied the antioxidant, glutathione (GSH), transcranially (as late as 3 hours post-injury) and observed a >50% reduction in parenchyma cell death. This treatment also preserved meningeal macrophages, maintained integrity of the glial limitans, and markedly reduced the innate CNS inflammatory reaction. These exciting data demonstrate that ROS are a major driving force in mTBI pathogenesis and that there is a window of opportunity available for treatment of this condition. Delaying treatment increases the amount of irreparable brain damage and likely exposes the CNS to increasingly synergistic pathways of neurotoxicity. In addition to researching sterile injury responses like TBI, we also study acute CNS diseases induced by microbes. We have recently obtained novel insights into a potentially fatal disease referred to as cerebral malaria (CM). CM is a severe complication of Plasmodium falciparum infection in humans that results in thousands of deaths each year. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using an animal model, we set out to understand the mechanics of this disease. During the development of CM, we revealed that parasite-specific CD8+ T cells attacked the surface of CNS blood vessels, which caused them to leak fluid into the brain and meninges. This resulted in brain swelling, which eventually damaged the brainstem - a fatal process referred to as cerebral herniation. We were able to therapeutically remove the disease-causing T cells from cerebral blood vessels using anti-adhesion molecule (LFA-1 / VLA-4) antibodies. This treatment was highly effective and prevented fatal disease. These data suggest that it might be possible to treat CM in humans using two FDA approved anti-adhesion molecule antibodies.